New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide

New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide

ABSTRACT: Although melanoma is a relatively chemoresistant malignancy, systemic
chemotherapy remains the primary treatment for metastatic melanoma. The
observation of vasculogenic mimicry in aggressive melanoma has prompted
investigation into using an antiangiogenic agent to enhance the antitumor
activity of chemotherapy in metastatic melanoma. Thalidomide (Thalomid) exhibits
antiangiogenic activity and other biological modulatory effects that may provide
additive or synergistic antitumor effects when given concurrently with
chemotherapy. A phase I/II study of thalidomide and temozolomide in the
treatment of metastatic melanoma is in progress. Preliminary results of this
combination therapy have shown significant antitumor activity, including some
striking responses in brain metastases. [ONCOLOGY
14(Suppl 13):25-28, 2000]

The survival of patients with metastatic melanoma varies widely,
ranging from only a few months to more than 10 years. Survival is primarily
dependent on the sites of the first metastases, the number of metastatic sites,
and responsiveness to treatment.[1] Melanoma can metastasize to virtually any
organ or tissue. However, the initial sites of metastases are most commonly the
skin, soft tissue, lymph nodes, and lung. The liver, bone, and brain are also
common, though less frequent, sites of initial relapse. Patients with
nonvisceral disease (ie, skin, lymph nodes, and lung metastases) have a better
median survival, ranging from 12 to 15 months, and are more likely to respond to
systemic therapy.[1,2] Patients with visceral disease (ie, liver, bone, and
brain metastases) have a median survival of only 3 to 4 months, and few respond
to treatment. In general, cure is not a realistic goal of treatment at this
stage of the disease. Therefore, treatment strategies must endeavor to preserve
quality of life while attempting to prolong life.

The primary treatment for patients with metastatic melanoma is
systemic therapy, in which response is associated with prolonged survival.
Systemic therapy includes single- and multiagent chemotherapy, immunotherapy,
and biochemotherapy. Melanoma is a relatively chemoresistant disease. The few
drugs that have antitumor activity in melanoma have not surpassed the 10% to 20%
response rates of dacarbazine (DTIC-Dome). Many combination chemotherapy
regimens have been reported to have higher response rates and to be more
effective for visceral metastases. However, most of the combination regimens are
associated with increased toxicity, with little evidence of improved survival
when compared to dacarbazine alone in phase III trials.[3] Even the addition of
high-dose tamoxifen (Nolvadex) to a combination regimen of cisplatin
(Platinol)/carmustine (BCNU)/dacarbazine (the Dartmouth regimen) did not improve
the response rate or survival in a phase III study.[4]

The administration of biological agents, such as interferon alfa
and interleukin-2, has been shown to produce 10% to 15% responses in advanced
melanoma with occasional durable complete response. Good-prognosis groups are
similar to those for chemotherapy, and include patients with good performance
status, and metastatic disease in soft tissue, skin, and lymph nodes.
Biochemotherapy or chemoimmunotherapythat is, the combination of chemotherapy
and biological agentsis another treatment strategy intended to improve the
antitumor effect of systemic therapy. The results of several phase II studies
have demonstrated high response rates and durable responses.

Recently, a randomized phase III study comparing a chemotherapy
regimen (composed of cisplatin, dacarbazine, and tamoxifen) with the same
chemotherapy plus high-dose interleukin-2 and interferon alfa was reported by
the surgery branch at the National Cancer Institute.[5] The response rate was
27% (4 out of 52 complete responses) for chemotherapy-treated patients and 44%
(3 out of 50 complete responses) for biochemotherapy-treated patients. However,
the tendency toward an increased response rate in patients who received
biochemotherapy did not translate into an increase in overall survival, and
there was, in fact, a trend for a survival advantage in patients receiving
chemotherapy alone (median survival: 10.7 vs 15.8 months). Because of the severe
toxicity associated with the biological agents, biochemotherapy is
contraindicated in elderly patients, or patients with central nervous system
(CNS) metastases, known cardiac disease, or symptomatic pulmonary disease.

Clearly, dacarbazine remains the most active drug and is the
standard chemotherapy for metastatic melanoma. However, response is seen
primarily in the skin, soft tissue, lymph nodes, and lung. It is estimated that
up to 70% of patients who die of metastatic melanoma have either known or
subclinical brain metastases. Like many other chemotherapy agents, dacarbazine
does not penetrate the blood-brain barrier; thus it is inactive against CNS
metastases. Furthermore, disease relapse in the CNS is often a major problem in
patients responding to chemotherapy.

Efforts to improve management of metastatic melanoma should
focus on the development of new antitumor agents and novel combination regimens.
Desirable characteristics of new treatment strategies include improved response
in visceral metastases, penetration of the blood-brain barrier with activity in
brain metastases, improved survival, and preservation of quality of life in the
form of reduced toxicity, improved tolerability, and ease of administration.

Temozolomide

Temozolomide, which was recently approved for the treatment of
refractory anaplastic astrocytoma, is an oral alternative to dacarbazine. The
agent exhibits approximately 100% oral bioavailability, penetrates the
blood-brain barrier, and has activity against brain tumors. The clinical
activity of temozolomide against melanoma was confirmed in a large randomized
study, when patients were treated with a 5-day schedule of either dacarbazine or
temozolomide.[6] More interestingly, patients who responded to temozolomide had
a four times lower incidence of melanoma relapse in the brain than did patients
who responded to dacarbazine.[7] As has been reported by Brock et al,[8] when
temozolomide is administered at an extended continuous schedule over a 7-week
period, it permits a 2.1-fold greater drug exposure over 4 weeks, in comparison
with the 5-day schedule repeated every 28 days.

In this phase I study, responses were observed in two of four
patients with metastatic melanoma: a partial response in a patient with
pulmonary metastases and a mixed response in a patient with CNS metastases. The
improved clinical activity is postulated to be related to the cumulative
depletion of O6-alkylguanine-DNA-alkyl-transferase,
a DNA repair protein involved in dacarbazine drug resistance of melanoma. It is
anticipated that temozolomide will replace dacarbazine as first-line treatment
for disseminated melanoma because of its ease of oral administration, improved
clinical activity, and ability to achieve adequate CNS penetration.

Thalidomide

Thalidomide has been shown to exert antiangiogenic effects,
including inhibition of angiogenesis induced by basic fibroblast growth factor
in the rabbit corneal micropocket assay.[9,10] Thalidomide has a number of other
biological activities that may contribute to its role as an effective agent in
treating melanoma; these include alteration of adhesion molecule expression,
suppression of tumor necrosis factor-alpha, increased production of
interleukin-10, and enhancement of cell-mediated immunity via direct
costimulation of T cells resulting in increased interferon gamma and
interleukin-12 production.[11-15]

Prospects for new combination regimens have been heightened by
the recent discovery of vasculogenic mimicry in aggressive human uveal and
cutaneous melanomas.[16] In particular, it has been shown that both primary and
metastatic melanomas can form tumor-cell-lined vascular channels, and that
this activity is correlated with tumor aggressiveness and clinical outcomes.
These findings suggest that the therapy directed against both endothelial- and
tumor-cell compartments of a tumor is more effective than therapy against tumor
cells only. Thus, combining standard chemotherapy with an antiangiogenic agent
has the potential to improve its antitumor effect for this chemoresistant
malignancy.

We initially used thalidomide on a compassionate-use basis in
select patients with disease progression who had received standard chemotherapy
or immunotherapy. One case was that of a 60-year-old woman who developed
multiple in-transit metastases in the leg and metastases in the inguinal lymph
nodes 37 years after a primary melanoma was removed from her ankle. She was
treated initially with inguinal lymphadenectomy and isolated limb perfusion with
carboplatin (Paraplatin).

Postoperatively, she received adjuvant high-dose interferon
therapy, but her disease recurred in the leg shortly after completion of 1 year
of adjuvant therapy; treatment included isolated limb perfusion with melphalan
(Alkeran) and tumor necrosis factor. Subsequently, her disease progressed in the
pelvis and retroperitoneum and interleukin-2 systemic therapy was used. However,
disease progression continued not only in the leg, pelvis, and retroperitoneum,
but new metastases had also developed in the liver and mesentery with massive
malignant ascites.

On initial presentation, the patient was cachectic with a
distended abdomen and had a Karnofsky performance status of 40%. She was started
on thalidomide at 100 mg/d and dacarbazine on an every-3-week schedule. After 3
months, not only did the ascites completely resolve, but significant shrinkage
of metastases in the liver and mesentery was observed, the retroperitoneal
adenopathy had completely resolved, and the pelvic adenopathy had markedly
improved.

The patient elected to discontinue dacarbazine, but remained on
thalidomide at a maximum dose of 200 mg/d. After an additional 3 months,
resolution of the liver metastases continued and virtually no adenopathy was
detected. The patient has now been on single-agent thalidomide at 200 mg/d for
over 1 year since stopping dacarbazine and recently has exhibited recurrence
only in the leg. These encouraging results prompted us to combine thalidomide
with the Dartmouth regimen in two additional patients who had disease
progression after treatment with this combination chemotherapy regimen;
treatment resulted in stable disease in one patient and a minor response in the
other.